The preclinical assessment of agents for the treatment of heart failure has been hampered by the lack of appropriate animal models. Previous models have either utilized non-clinically relevant insults to induce the disease state, or have failed to produce controllable, stable and predictable damage. Pressure overloading to induce ventricular hypertrophy and failure, produced by a variety of techniques including corticosteroid administration, renal artery occlusion, unilateral nephrectomy with contralateral occlusion of the renal artery, and most extensively banding of major outflow tracts such as the aorta, has been used in a variety of species including rat, cat and dog (Smith and Nutall, Cardiovascular Research 19: 181-186, 1985).
However, acute severe fixed afterload augmentation in animal models probably differs significantly from the gradual events that occur with pressure overload failure in man. The major limitation of animal pressure overload models include the propensity for the development of hypertrophy but not failure and/or a protracted time frame for the development of failure. Volume overloading produced by arteriovenous fistulae and valvular incompetence has been used to induce heart failure in dogs; however, this method has been limited by difficulty in controlling the degree of cardiac damage (Smith and Nutall, Cardiovascular Research 19: 181-186, 1985).
Cardiotoxic agents, including doxorubicin, have been used in several species including rat and dog to induce heart failure. This approach is limited by difficulty in controlling dose of cardiotoxic agent to induce sufficient but not excessive damage, extracardiac toxicity and the production of calcium overload-injury that may render the model unsuitable for the assessment of positive inotropic agents (Czarnecki, Comparative Biochemistry and Physiology 79C: 9-14, 1984; Smith and Nutall, Cardiovascular Research 19: 181-186, 1985). Several experimental procedures have been utilized to effect coronary artery occlusion, myocardial ischemia and resultant heart failure primarily in rats and dogs. These procedures include direct coronary ligation, embolism with liquid mercury, injection of preformed thrombus, wedged catheters, and sequential coronary microembolization with microspheres (Khomaziuk et al, Kardiologiya 5: 19-23, 1965; Rees and Redding, Cardiovascular Research 2: 43-53, 1968; Lumicao et al, American Journal of Medical Science 261: 27-40, 1971; Millner et al, Annals of Thoracic Surgery 52: 78-83, 1991; Sabbah et al, American Journal of Physiology 260: H1379-H1384, 1991). Problems associated with coronary artery ligation/ischemia models of heart failure include the inability of ischemic rodent models to develop myocardial dysfunction which meets the hemodynamic criteria of heart failure, as well as a high degree of malignant arrhythmia and mortality associated with myocardial ischemia. Damage to the heart from repeated DC shocks has been shown to induce heart failure in dogs (McDonald et al, Journal of the American College of Cardiology 19: 460-467, 1992); however the clinical relevance of this method of damage is uncertain.
Recently, several laboratories have adopted the method of rapid ventricular pacing-induced heart failure in dogs (Riegger and Liebau, Clinical Science 62: 465-469, 1982). One prominent criticism of the pacing-induced dog failure model is that while it does induce a predictable, controllable degree of myocardial failure, this condition is reversible with the termination of pacing. Also, the underlying mechanism for the development of failure in the pacing model is not understood at this time.